Development of cebranopadol, a potent dual MOP/NOP agonist, for the treatment of Opioid Use Disorder (OUD)

开发cebranopadol，一种有效的双重MOP/NOP激动剂，用于治疗阿片类药物使用障碍（OUD）

• 批准号: 10759100
• 负责人: Mark K Greenwald
• 金额: $ 332.96万
• 依托单位: PARK THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10759100
• 关键词: Acute; Address; Affect; Affinity; Agonist; Apnea; Behavior; Binding; Breathing; Buprenorphine; Clinical; Clinical Data; Clinical Research; Confidence Intervals; Crossover Design; Data; Development; Dosage Forms; Dose; Double-Blind Method; Drug Metabolic Detoxication; Evaluation; Fentanyl; Future; Heroin; Hour; Human; Hydromorphone; Incidence; Intravenous; Maintenance; Measures; Mediating; Methadone; Morphine; Motor; Naltrexone; ORL1 receptor; Opiate Addiction; Opioid; Opioid Peptide; Opioid Receptor; Oral; Oral Administration; Outcome Measure; Overdose; Oxycodone; Oxygen; Pain; Participant; Patients; Peptide Receptor; Persons; Pharmaceutical Preparations; Pharmacotherapy; Phase; Physical Dependence; Placebos; Precipitation; Randomized; Rattus; Receptor Activation; Recreation; Regimen; Respiratory physiology; Risk; Safety; Schedule; Self Administration; Signs and Symptoms; Solid; Testing; Therapeutic; Tramadol; Treatment Efficacy; Ventilatory Depression; Visual; Withdrawal; Withdrawal Symptom; abuse liability; addiction; alternative treatment; analog; antagonist; attenuation; cocaine self-administration; craving; effective therapy; efficacy evaluation; efficacy study; experience; fentanyl self-administration; improved; intravenous administration; meetings; morphine administration; mortality; nociceptin; opiate tolerance; opioid epidemic; opioid injection; opioid misuse; opioid overdose; opioid use; opioid use disorder; opioid user; opioid withdrawal; overdose death; overdose risk; preclinical safety; preclinical study; primary outcome; programs; receptor; safety study; synthetic drug; verbal

ABSTRACT/SUMMARY The U.S. is experiencing a crisis of opioid misuse, addiction, and overdose; in the most recent year, there were over 100,000 drug-related overdose deaths, 75% of which involved opioids. Current pharmacotherapies for opioid use disorder (OUD) target mu opioid peptide (MOP) receptors, one of five classes of opioid receptors. These therapies include the full MOP agonist methadone, the partial MOP agonist buprenorphine, and the MOP antagonist naltrexone. There are several drawbacks in using these medications to treat OUD, which include the potential for abuse, development of physical dependence, and risk of overdose, particularly for methadone and buprenorphine. Buprenorphine and naltrexone also trigger severe withdrawal symptoms. There is thus an urgent need for an improved therapeutic for the treatment of OUD. Cebranopadol (TRN-228) is a first-in-class synthetic drug developed for its dual-action mechanism in treating pain, mediated by high affinity and potency for both MOP and nociceptin/orphanin FQ receptor (NOP). NOP receptor activation has been associated with reduced development of tolerance, abuse-related behavior, addiction, and physical dependence. In this UG3/UH3 proposal, Park Therapeutics is developing TRN-228 as a first-in-class dual MOP/NOP agonist that can be used as a safe and effective treatment for OUD. Preliminary nonclinical and clinical data indicate that cebranopadol has low potential for abuse and physical dependence and produces milder respiratory depression compared to pure MOP agonists such as morphine and oxycodone. TRN-228 also decreases morphine, heroin, and cocaine self-administration in rats and did not induce withdrawal when given to opioid-dependent rats. The UG3 phase of this proposal will test whether oral TRN-228 is a safe and potentially effective alternative treatment for OUD, based on the following Specific Aims: 1) determining the effects of TRN-228 on intravenous fentanyl self-administration and fentanyl-induced respiratory depression in opioid-dependent rats, 2) determining the IV abuse potential of TRN-228, and 3) assessing the ability of TRN-228 to suppress withdrawal. Upon meeting the UG3 Go/No-Go milestones, Park will progress to the UH3 phase which will demonstrate the therapeutic efficacy of TRN-228 in decreasing opioid use with low risk of withdrawal or abuse, which will be accomplished by 4) determining the effects of TRN-228 on fentanyl-induced respiratory depression in opioid-tolerant participants and 5) evaluating the ability of TRN-228 to block the subjective effects of hydromorphone. These studies will significantly advance the field by establishing the safety and preliminary efficacy of TRN-228. Successful completion of these aims will guide future efforts to establish a clinical program for FDA approval.

摘要/摘要 美国正遇到阿片类药物滥用，成瘾和过量的危机。在最近的一年中，有 超过100,000种与药物有关的过量死亡，其中75％涉及阿片类药物。当前的药物治疗 阿片类药物使用障碍（OUD）靶向MU阿片类肽（MOP）受体，这是五种阿片类药物受体之一。 这些疗法包括完整的MOP激动剂美沙酮，部分MOP激动剂丁丙诺啡和MOP 拮抗剂纳曲酮。使用这些药物治疗OUD有几个缺点，其中包括 滥用的潜力，身体依赖的发展以及服用过量的风险，特别是美沙酮和 丁丙诺啡。丁丙诺啡和纳曲酮也会引发严重的戒断症状。因此有一个紧急的 需要改进的治疗方法。 Cebranopadol（TRN-228）是第一类合成 为治疗疼痛的双重作用机制而开发的药物，由高亲和力和两者的效力介导 MOP和Nocteptin/Orphanin FQ受体（NOP）。 NOP受体激活与减少有关 宽容，与滥用相关的行为，成瘾和身体依赖的发展。在这个UG3/UH3中 提案，Park Therapeutics正在开发TRN-228作为一类双拖把/NOP激动剂，可以 用作OUD的安全有效治疗。初步非临床和临床数据表明 Cebranopadol对滥用和身体依赖的潜力较低，并产生温和的呼吸抑郁症 与吗啡和羟考酮等纯MOP激动剂相比。 TRN-228还减少了吗啡，海洛因， 和可卡因在大鼠中的自我给药，并且在依赖阿片类药物依赖性大鼠时不会引起戒断。这 该提案的UG3阶段将测试口服TRN-228是否是安全且潜在的有效替代治疗 对于OUD，基于以下特定目的：1）确定TRN-228对静脉注射芬太尼的影响 阿片类药物依赖性大鼠的自我给药和芬太尼诱导的呼吸抑制，2）确定IV TRN-228的滥用潜力和3）评估TRN-228抑制退出的能力。见面 ug3 go/no-go里程碑，公园将前进到UH3阶段，这将证明治疗功效 TRN-228减少阿片类药物的使用，而戒断或滥用的风险低，这将在4下完成） 确定TRN-228对芬太尼诱导的呼吸道抑郁症对阿片类药物耐受性参与者的影响 5）评估TRN-228阻止氢球主观效应的能力。这些研究会 通过建立TRN-228的安全性和初步疗效来显着提高该领域。成功的 这些目标的完成将指导未来的努力，以建立FDA批准的临床计划。